Hydroxyeicosatrienoic acid compounds and their use as therapeutic agents

1. A compound of Formula (0), or a pharmaceutically acceptable salt thereof:

wherein:

A is —COOR 1 , —OSO 3 R 1 , —OPO 3 (R 1 ) 2 , or -G-HET;

B is a bond each R 1 independently is H or C 1−6 alkyl;

R 2 is H or OH;

each —is a single or double bond, provided that (i) when —at bond 2 is a single bond, then —at bond 1 is a trans double bond and R 2 is OH, and (ii) when —at bond 1 is a single bond, then —at bond 2 is a cis double bond and R 2 is H;

HET is an unsubstituted or substituted 5 to 10-membered heteroaryl group having 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, S, or O;

G is O, S, NH, or absent;

C x is an alkylene group having x carbon atoms;

C y is an alkyl group having y carbon atoms;

x is 3, 4, 5, 6, or 7;

y is 4, 5, 6, 7;

and each carbon atom of the compound of Formula (0) independently is unsubstituted or substituted with one or more deuterium or fluorine atoms;

with the proviso that when x is 6, y is 5, and each carbon atom of Formula (I) is unsubstituted, then A is not —COOH.

2. The compound of claim 1 , having a Formula (I) or (II):

3. The compound of claim 1 , wherein A is —COOR 1 , —OSO 3 R 1 , or —OPO 3 (R 1 ) 2 .

4. The compound of claim 1 , wherein R 1 is H or CH 3 .

5. The compound of claim 1 , wherein A is -G-HET.

6. The compound of claim 5 , wherein HET is a 5- or 6-membered heteroaryl group.

7. The compound of claim 6 , wherein HET is tetrazolyl, triazolyl, or isoxazolyl.

8. The compound of claim 1 , wherein G is absent.

9. The compound of claim 1 , wherein G is O or S.

10. The compound of claim 1 , wherein x is 4, 5, or 6; and/or y is 5.

11. The compound of claim 1 , wherein at least one carbon atom is substituted with deuterium; and/or at least one carbon atom is substituted with fluorine.

12. The compound of claim 11 , wherein the carbon atom at position 13 is disubstituted with deuterium or fluorine.

13. The compound of claim 1 , wherein each carbon atom is mono- or disubstituted with either deuterium or fluorine.

14. The compound of claim 2 , wherein the compound is of Formula 1 and has a structure selected from the group consisting of:

or wherein the compound is of Formula (II) and has a structure selected from the group consisting of:

15. A composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

16. A method of treating a thrombotic disorder, preventing thrombosis, or treating thrombocytopenia in a subject having a thrombotic disorder thereof comprising administering a compound selected from 12(S)-hydroxy-8Z, 10E, 14Z-eicosatrienoic acid, a compound of claim 1 , or a pharmaceutically acceptable salt of any of the foregoing to the subject in an amount effective to inhibit thrombus formation and/or loss of platelet cells while maintaining hemostasis.

17. The method of claim 16 , wherein the subject has a thrombotic disorder selected from arterial thrombosis, deep vein thrombosis, pulmonary embolism, ischemic stroke, immune thrombocytopenia (ITP), Heparin-induced thrombocytopenia (HIT), and Heparin-induced thrombocytopenia and thrombosis (HITT).

18. The method of claim 16 , comprising administering the compound to the subject before, during, and/or after a surgical procedure.

19. The method of claim 16 , comprising administering the compound in an amount effective to:

(i) inhibit platelet aggregation; or

(ii) inhibit platelet integrin activation; or

(iii) inhibit Rap1 activation; or

(iv) activate G α s -linked G Protein-coupled receptors (GPCRs); or

(v) activate cAMP; or

(vi) activate protein kinase A (PKA); or

(vii) inhibit thrombus growth; or

(viii) combinations thereof.

20. The method of claim 16 , comprising administering the compound to the subject at a dose between about 0.1 mg/kg and about 50 mg/kg and/or administering the compound orally or intravenously.